BioXcel Therapeutics, Inc. (BTAI)

Study Update

← View all transcripts

May 22, 2019

Okay. Well, good morning, everyone, and thank you all for joining us today to discuss the potential of our lead neuroscience program, Dxpl0501, which is our proprietary sublingual thin film formulation of dexmedetomidine. So, just for it's the last time I'm going to say dexmedetomidine. I'm doing it for a certain person in this room. I know he knows it. So, we'll call it dex from this point on. So, dexmedetomidine, dex, we'll call it dex, okay, which is being developed for acute treatment of agitation across neuropsychiatric diseases. Today, we look forward to discussing the global clinical development plans, the market opportunity, preliminary data results from our Phase 1 study, commercialization strategy as well as our indication expansion plans for BXCL501. With us today is an outstanding panel of key opinion leaders that will contribute to the acute agitation overview with respect to each of the proposed neuropsychiatric indications. But for now, let me turn the podium over to our Chief Executive Officer, Doctor. Vimal Mehta to provide an overview of our strategy and vision for BXCL501. Thank you, Frank. Good morning, everyone. Thank you for joining us today here and everyone who is joining us via webcast. I'm so excited and thrilled to be here to give you the overview of BioXcel Therapeutics. Just to give you a quick history of BioXcel Therapeutics, biaxial therapeutics went public in March of 2018. We are here today. We are moving our 501 program into the Phase 2, as well as we expect those results to come out in Q3 of this year and then we'll be in a position to move this program into the registration trial. So we are very excited. I'm Vimal Mehta, I'm CEO and Co Founder of BioXcel Therapeutics. Before I begin, I'd like to remind everyone of the safe harbor statement that as we will be making forward looking statements. So Frank already went through the agenda. This is a quick recap what we will be covering for today, starting with the strategy and vision that I will cover and then we'll go into the program with the key opinion leaders and then clinical program as well as then we have a Q and A for the KOL panel. So in terms of the BXCL strategy and vision, where we are today, we feel very excited that there is a very broad potential to go into multiple neuropsychiatric disorder from where the agitation results. And our product is a proprietary sublingual thin film. This film was developed and this film has immediate release film with Muca addition. It's a proprietary technology how we put in the decks on the film. It delivers broad range of doses and it's flexible for combination dosing and therapy. You can see the film is green in color. It's little minty in taste and it's right kind of a size to put it under the sublingual portion of the patients basically. So in terms of status of the film in, we have recently transitioned our process to an automated process because initially we made film to do our Phase 1 studies and we are ready to initiate our Phase 2 studies with the film. Then we needed lot of samples of the film for our Phase 3 as well as getting ready for the commercial readiness. So now process has been transitioned to an automated process and we feel very comfortable that the timelines we have projected that we will initiate our Phase III trials this year will be ready with the materials. So in terms of our development plan for this product, we are at this stage Phase 2 initiating schizophrenia. As I mentioned on Monday, we announced the results from the Phase 1 study where we covered the PK exposure levels as well as the safety for the product. And this study, we will get the data readout in Q3 of this year. It's a short study. And Rob will go in detail about the design of the study and how many sites and how many patients we are planning to enroll for this study and that will help us power our Phase 3 study, which will be 1 in schizophrenia patients and other 1 in bipolar. Phase 2 is only in schizophrenia. This data will be sufficient to initiate registration trial using 1 in schizophrenia, 1 in bipolar disorder with a potential filing of the NDA in second half of twenty twenty. And we anticipate the commercial launch will be in 2021. Those are the timeline for our first indication is schizophrenia and bipolar. In addition, we have done human proof of concept using the IV Dex, a current form of the drug in all these indications like dementia, in opioid withdrawal and delirium work was published by investigators. So we have good human proof of concept using the current form of the drug. So clinical plans are under development for all these three indications and we anticipate that we will roll out the clinical plans specifically the way we have done it for schizophrenia and bipolar in 2019. Let me just flip to the right slide. Just one more. I think okay, now it's working. So in terms of the commercial opportunity, when we did the analysis of these four indication that we are discussing here, we looked at how many patients are at risk and this is done by our 3 commercialization team. So they looked at about 18,000,000 patients are at risk, About 8,000,000 patients experience agitation. And agitation is a spectrum, which is mild, moderate and very aggressive. So we believe and what we have put in here is a moderate agitation where the film will be amenable, the patient that are going to be cooperative. So they are cooperative patient who are in mild to moderate and they are uncooperative patients. So that's where we are targeting the patient pool. We do believe that it's not only the moderate, there are some patients who are going to be mild to moderate. They will be able to use the film because they cannot be de escalated using the verbal de escalation what normally physicians do. And they are going to be patient who are going to be moderate to aggressive, but they still may be able to take the film. So best way Rob tells is the patient who will use this film will be who is willing to take the film or who can take the film. So that's kind of our target patient population. But moderate we call as a cohort population. These patients experience multiple episodes per year. We know schizophrenia and bipolar patients have multiple episodes, they end up in the emergency room. Then dementia patient, it can vary depending on where the state of dementia is. I know our key panel leaders are going to talk about it, so I will skip that. And opioid withdrawal in detoxification, it could be a 5 to 7 day period. And similarly, delirium, Doctor. Maurizio will talk about it, how these what the needs of these patients is. So we see this as a pretty large opportunity and our development is a 505(3) development pathway and it's a very rapid development pathway, what I showed you in the previous slide. And today, I'm joined by my team, Frank Yocca, who is Chief Scientific Officer, he is here Vince O'Neil, he is Chief Medical Officer Chetan Latya, who is Head of Clinical Pharmacology and Regulatory Affairs Robert Singer, he is VP of Clinical Development David Henley, VP of Global Pharmaceutical Development and Operations. He developed the film. Pascal recently joined us and he's doing all the pre commercial strategy for 501. He is VP of Commercial Development and Medical Affairs. And finally, Doctor. Peter Mueller, who doesn't need any introduction. He is the Chairman of the Board and he has joined us. All of you know him from Boehringer Ingelheim as well as the Vertex Day that he has very excellent background in bringing multiple drugs to the NDA, getting them approved and we are very happy that we have the oversight of Doctor. Mueller to help us build BioXcel Therapeutics. In terms of the vision of the company, we want to bring one NDA every 2 to 3 years. That's the vision of the company. And how can we achieve that? We have an AI platform that we use to identify 501, which is our lead neuroscience product. And then we have immuno oncology asset, which is for working on the innate immunity activator. So those are the 2 lead assets. 501 is our example of executing on our vision of the biaxial therapeutic. And then we have 2 ongoing trials on 701 and one more trial will be started very soon for our leading in oncology assay. So with that, I will stop and I will pass it on back to Frank. So, what we're going to do is I'll talk a little bit about the concept and what we were trying to achieve in actually developing 501. And our goal here was we were looking at agitation as a problem that was going to grow. It was going to become even bigger. Why? Because in the neuroscience field, you not only have problems with agitation coming from the psychiatric side of the neuroscience limb, but you also have problems now, growing problems in the geriatric side of things. And with these diseases not being able to be treated, this is going to be a real problem and not just for the patient, but for caregivers and for families. So the idea was, can we now turn our attention to these behavioral issues? And the one big behavioral issue is agitation. So when we looked at the drugs and we looked at the problems that physicians and clinicians were facing with the current drugs, we said, can we make this better? Can we come up with a 21st century type drug that fits all of the needs, both psychiatric as well as geriatric? And basically, there have been a number of consensus opinion groups that have been put together that have talked about this problem, have been made up of psychiatrists, emergency room physicians. And these are the different characteristics that they came up with. They want something that's non invasive. They want something that will calm the patient, not just sedate the patient. It has to be easy to administer. It has to have a rapid onset, non traumatic. What we mean by non traumatic is that introducing a syringe into an agitated situation is not good for the patient and it's not good for the caregiver either. So could we come up with something that's a non injectable? Has to have a good safety profile, a favorable tolerability and then would be something that once a patient uses it that they would have a preference to actually go back to that, because a lot of these patients, particularly the psychiatric patients, know when they're heading down this path and the idea is that can they use something that they feel comfortable with and abort the situation. So this is where VXCL501 came in. It has the properties that fit a lot of that criteria that we have listed here. So what we thought we would do today is have key experts in the areas that we think DXCL501 could play a role. And what I mean by that is that in different indications where agitation is a problem. So what we're talking about is psychiatry, schizophrenia and bipolar, which is really our first approach that we're doing dementia, which is also becoming a huge problem opiate withdrawal, where these patients who are withdrawing from opiates and are in that withdrawal system suffer severe agitation. But not only that, it seems to be a locus centric event where BXCL501 does its work. And then finally, delirium, where you have these anesthetized geriatric patients who come out of surgery and they're delirious and it really a lot of times these patients never come out. And the question is could BXCL501 in a different format than an IV play a role? So with that in mind, we have our 4 ks O wells that I'll introduce to you. And at one other time, they'll come up and speak to these problems that agitation causes in their areas. So with that in mind, our first guest this morning is Doctor. Sheldon Presskorn, who will discuss acute agitation in schizophrenia and bipolar disease. Doctor. Presskorn is President and Chief Executive Officer of Worldwide Psychopharmacology Consultants and Professor of Psychiatry at the University of Kansas Medicine Wichita. He's one of the world's leading experts in psychiatric drug development. And over the last 25 years, Doctor. Presskorn has been a principal investigator on numerous antidepressant and anti psychotic medications marketed in the United States. He served on the U. S. Food and Drug Psychopharmacology Advisory Committee and presented 12 new drug applications to 8 different FDA advisory committees. So what Doctor. Presscom will do is talk for about 10 minutes. What I'd like you to do is to hold your questions until we have the panel come up so that they can go through their presentation. So with that in mind, Sheldon? Thank you very much, Frank. And you've got the remote. Okay. Yes, very good. Well, it's a pleasure for me to be here with you today. So one, I'm sure you've all seen agitated individuals. You possibly passed some in the street today on the way here. So I certainly have over 4 years of academic medicine. One stands out in particular, it was after hours. Everybody had gone. My desk was sit back away from the door by several feet. I could smell the bourbon when the person entered the room. He came over to my desk, sat down and explained that he wanted to have a serious conversation with me. To emphasize the point, he pulled out his 9 millimeter automatic pistol and his clip, which was loaded. He then chambered around and for the next hour, we had a meaningful conversation. So that is one example of agitation of which there are many. I wish I had Deck's film on my desk and could have offered it to him, but that wasn't possible at that moment. So, okay. So psychomotor agitation is an unmet medical need in terms of being able to give medicines that are well tolerated and do not actually worsen the condition early on. So Benzodiazepines, which you're probably familiar with, unfortunately, at the early phase of Benzodiazepines getting into your your until you get to sedation that you may act on your agitation. So it's characterized by motor restlessness and irritability. That patient, by the way, was agitated that I just described to you. 2, aggression and violence. We've already gone through the statistics. 10% to 31% of all patients with schizophrenia or related psychotic disorders exhibit aggressive or violent behavior. You encounter them, as I say, on the streets, you encounter them in the emergency room, you encounter them on the floors, you encounter them in the outpatient clinic. And acute episodes of psychomotor agitation represent a serious number, a substantial number of emergency room department visits, because they're often brought in because they're agitated. Agitation has medical cost. First of all, it can cause death, it can cause injury, and longer hospital stays, increased medication consumption, higher readmission rates, and increased number of violent incidences against staff and others. So one can calculate the cost of this and compare that against the cost of the medication. The treatment algorithm, a need for pharmacologic intervention, if the answer is yes, as it would have been in that case I gave you. Cause of agitation of psychiatric disorder, in this case, there was an underlying psychiatric disorder fueled a bit by bourbon. Is the patient cooperative? He may have actually taken Dex, if I had been able to offer it to him. If the patient is cooperative, then the current options are inhaled antipsychotics, there's a formulation of that, some lingual antipsychotics, an oral antipsychotic or oral Benzodiazepines. I've already given you one of the limitations of Benzodiazepines, they intoxicate you. And the first thing that happens is you lose your and quite varied depending upon the nature of the antipsychotic. And I won't go into all of those for you, except if you want to ask questions during the Q and A sessions. Over on the right hand side, we have the characteristics of an ideal drug for the treatment of psychomotor agitation, calm without sedation, which Frank has already emphasized, directly targets the hyperarousal system as a pathophysiological mechanism underlying the agitation, non traumatic and non invasive. We've discussed that, particularly as it relates to intramuscular administration of drugs, which generally you only do when you have the individual in 4 point restraints. Rapid onset of action, unlikely to cause respiratory depression, which Benzodiazepines can do, particularly if you push the dose rapidly and unlikely adverse cardiovascular or more motor events. By the way, atypical antipsychotics, if you're dealing with high potency D2 blockers, one of the problems they can cause is a condition we call akathisia. And akathisia is motor restlessness. And motor restlessness can look a lot like agitation. It's also extremely uncomfortable for the patient. I actually had a patient come in and say, if I had to continue this way, I would shoot myself. So it literally is a significant problem. So the prediction, you can see the check boxes for yes and no, but the prediction is dex on sublingual film will exhibit a superior profile compared to these currently used drugs for the acute treatment of agitation in a wide variety of patients, not just schizophrenia and bipolar disorder. Now, if I were you, I probably would wonder, well, how can one drug do all of this? How is that possible? Well, to understand that, this is the brain. And right here, this green dot is the locus coeruleus. And the locus coeruleus is your sympathetic ganglion in your brain. It is there to arouse you, to control your respiratory drive and your cardiovascular output. It is like the fire alarm system in your brain. And when it detects that you are getting acidotic, it fires off and that's a panic attack. In the morning, it awakes you. It's part of the arousal system for your awakening. The downward projections drive your cardiovascular system to increase cardiac output to vasoconstrict you, and it drives your respiratory system to be inhaling more and you can hyperventilate. The upward projections alert your brain. So this is a key component to agitation. So how does dex work? Dex works by binding to the Alpha-two adrenergic system. Now, this system has a feedback loop. So it has an auto control to not get overly active, but sometimes that doesn't work. So you have norepinephrine, what we call alpha-two receptors on the cell bodies. And when your norepinephrine gets too high, you decrease the firing rate of these neurons. Dex works to decrease the firing rate of these neurons. So it's central to the whole concept of over arousal and agitation. And that's how it can work in so many different conditions. So it's a sublingual film intended for patients from mild to moderate agitation, treats the underlying cause, which is this hyper arousal system, which your brain has in it for perfectly good reasons, but it can get overactive. So goals of therapy, increased cooperation of the mildly agitated patient, prevent escalation to more severe. And then we can look at how we grade patients. So a patient may be mild, meaning they have nervousness, they're tense, they're grumpy, they're anxious. So there's a continuum between anxiety and severe agitation, all driven by the system I just described to you. Moderate, they may be insulting. They may be unable to respect interpersonal space. They may be frightened and in danger. At this point, they may actually in both of these conditions, they may actually want treatment to calm themselves down. I'm too irritable. I'm too on edge. I need to sort of feel more calm. And then you get into the severe cases where you have violent aggression, confused, desperate, and where they can cause harm to themselves and harm to others. So this simply shows you that as Vimal mentioned, we've looked at this in individuals with agitation and schizophrenia. We've looked at it in agitation in individuals with senile dementia of the Alzheimer's type and an opioid withdrawal. This is from the schizophrenia study. This here is a reduction in the score of agitation. It's reflected in what's called the PEC score, which is simply a subscale of the positive and negative symptoms of schizophrenia. That's how you get PANSS, positive and negative symptoms of schizophrenia. And it is the excitatory component. So P stands for PANS, E stands for excitatory, and C stands for the component subscale. And the reduction in this represents onset of therapeutic action. Now over here is arousal. And the key thing here is that the drug has an anti agitation effect as reflected by these drops with very few patients actually having a decrease in their arousal. So here is where you get where you end up starting to have the arousal go up. So the bars represent arousal, the dash line represents a reduction in agitation. And you nicely see the anti agitation effect occurring in most individuals well before they have an impact. By the way, a RAS of -one means you're drowsy, drowsy. Not a ton bit. You're simply more likely to fall asleep if you're not stimulated, but you're not somebody who needs loud. So a RAS of minus 2 would be I would have to call your name vigorously to wake you up. And as soon as I stopped, you would drop back to sleep. This is simple drowsiness. All right. I think I finished and probably on time and even with a vignette. Thank you so much. The sympathetic system described to me in such an elegant way. So, let's turn our attention now to dementia and Doctor. George Grossberg, who is our 2nd KOL, who will discuss the area of acute agitation in dementia. Doctor. Grossberg is a Professor and Director of Geriatric Psychiatry at St. Louis University of Medicine. Doctor. Grossberg has served as a consultant for central nervous system disorders to companies such as Abbott, AstraZeneca, Bayer, Forest, Janssen, Lilly, Novartis, Organon, Syntelabo. His area of clinical expertise includes later life depression, delirium, psychiatry in the nursing home setting and geriatric psychopharmacology. His research interests include behavioral symptoms in Alzheimer's disease and new treatments for neurocognitive disorders. In addition, he is also President of the American Association For Geriatric Psychiatry and the International Psycho Geriatric Association. So with that, George? Thank you very much. Nice to be here. Thank you for inviting me. Important topic. Before I start, I'm just being that Sheldon started with a vignette, I just thought of an interesting vignette. I saw a family recently who brought their mom to me for a more definitive diagnosis. They had been to their she was in her early 80s. They had been to their primary care physician. And what they basically told me was, there was good news and bad news. The good news was that they were told it was not Alzheimer's disease, but the bad news was that mom had dementia. So I knew right away that she had a totally un thorough, non appropriate evaluation because the reality is, is that over 3 quarters of all dementias, which is have a wastebasket diagnosis, indeed are secondary to Alzheimer's disease. So my presentation today, assuming I can advance my slides, okay, let's go back, is going to be on Alzheimer's disease slash dementia because we're not just looking at Alzheimer's disease, although that's the big target. We're also looking at things like Lewy body dementia. Many of you have heard about that. It's been in the news because some famous people at autopsy were diagnosed with that. We're also looking at what's called vascular dementia or neurocognitive disorder, small strokes or larger strokes causing cognitive impairment in an older adult. So all of these and there are Parkinson's dementia, there are many other frontotemporal dementia, many other dementias. But again, think Alzheimer's disease because that's really the big one. And I would venture to say that there probably isn't a single person in this room that hasn't been personally touched by Alzheimer's disease. You know someone that has it, you maybe have a family member who has it. It's very different than other diseases that receive a lot of attention and a lot of federal funding like AIDS, for example, which is a horrible disease. We've made great progress, but most of us may not personally have been impacted. But with Alzheimer's disease and dementia, it's very, very different. Just before, when we were having breakfast, I was talking with one of you about a family member who gets with Alzheimer's disease or with dementia who gets agitated whenever the caregivers try to give her a shower or a bath or to get her bathed in the morning. We call that agitation with hands on care. It's extremely common, extremely common, both at home when the family is taking care of a loved one, in the memory care setting, in the assisted living setting, in the nursing home environment. We have 3 teaching nursing homes in St. Louis. I'm going to come and visit some of those. And probably 80% to 90% of all the residents in those nursing homes have some type of dementia. When I take 3rd year medical students with me and we do teaching rounds in the nursing home and one of the nursing homes has a special dementia unit. They assume that everybody with dementia is only on that 20 bed unit of a 240 bed nursing home. And I tell them, no, those are the more severe patients. 90% of everyone is cognitively impaired. So it's the number one reason now for winding up in assisted living, memory care or in the spectrum of long term care, including nursing homes. Okay. So these are my disclosures. You heard about some of those. So I work with small and large companies to help them to develop new compounds, primarily for Alzheimer's disease. This is oops, now we skipped that slide. Sorry about the technical issues. Is this supposed to be working? You didn't have any trouble with it, shall we? Let's go back to the one before, trying to go backwards, but there we go. All right. So the scope of the problem, and again, I don't need to belabor this, but I do want to emphasize that this is not merely kind of a U. S. Problem, the problem of Alzheimer's disease. It's really been called a worldwide epidemic. And I would point to, in particular, look at the dramatic growth in numbers in Asia. In emerging countries, I consult to a number of institutions in India. I go a couple of times a year. I started a program at King George Medical College looking at in Lucknow, looking at late life mental disorders and advising the Indian government about the growing problem of Alzheimer's disease and dementia. Because there too, and in China and other emerging countries, people are living longer and longer. And they've not really addressed the growing problem of Alzheimer's disease and dementia and their elders. And we too in the U. S. Are not quite ready for it. And the big problem is what we're going to be talking about in just a moment is trying to control the behavioral manifestations. We don't have a cure. We don't have a way to halt the disease. We don't have a way to undo the damage that's already been done. What we can do is make it easier for caregivers, for families, professional caregivers to take care of their loved ones, take care of our elders with this growing population of Alzheimer's disease or dementia. So just some kind of quick facts. This is from the U. S. Alzheimer's Association, and I'm on the Board of our Alzheimer's Association in St. Louis and I've been very involved with them. I would advise many of you who are interested specifically in dementia or Alzheimer's disease to go to the Annual Alzheimer's Association International Conference. It's always held in July. This coming July, it will be in Los Angeles. Sometimes it's held in Europe, but most of the time in the U. S, particularly in Chicago, where the association is based. You can, by going to that 4 day meeting, get a feel for the broad spectrum of disorders that we're talking about and what kind of research is happening all over the world. Especially interesting are the posters. The business media is very heavily represented and you guys are getting close to at least beginning to present maybe some data in this population at that meeting. 6th leading cause of death in the United States, a very, very expensive disease. One of the costs that's often not included in the overall cost of Alzheimer's disease is all the unpaid caregiver time. The family member, and I can tell you that I have people that come to me, an adult daughter or a son, who has to take off from work to bring their mom for a routine follow-up or for medication management or take off for work to get a second opinion or to get them diagnosed or worked up or evaluated. Some are living with family and the family is putting in tons of time, which is not cheap, to take care of their loved one. What we've also seen, as you see in the 3rd bullet, is that over the last decade or a little more than the last decade or 2, Heart disease, we're making a lot of progress in healthcare. So less and less people are dying of heart disease, heart attacks and strokes, but unfortunately, more and more deaths from Alzheimer's disease, at least over the past couple of decades. And 1 in 3 seniors who lives long enough dies of Alzheimer's disease, which is more than a couple of common cancers, breast and prostate combined. Huge costs, this is 2019 costs, dollars 2.90 billion and it's something that happens literally every minute. It's a huge disorder. This is a study, I'll walk you through this, kind of award winning study. We actually got a lot of kudos for this that we did a number of years ago. And what was unique about this study is we took 100 autopsy confirmed Alzheimer's patients. So we knew that at autopsy, at death, they definitively had Alzheimer's disease and nothing else was responsible for the brain disease. And we put these 100 people under a microscope. This is called the timeline diagram. So what we're looking at here are months before the diagnosis. This is the time of diagnosis of Alzheimer's disease. Keep in mind that even today, even today, this is a study that was done in 1996, but even today, patients are not diagnosed early. By the time families bring their mom or dad or grandma or grandpa to meet and we eventually diagnose dementia or Alzheimer's disease, it's been going on for 2 or 3 years or longer. And you wonder, well, why did you we ask, how long has it been since you've been concerned about mom's memory? Oh, it's been going on for at least 2 or 3 years. Another daughter might say, gee, I remember 4 years ago, I came home for Christmas and I was noticing that mom wasn't quite right. But we figured, what the heck, she's 85. You're going to be a little forgetful when you get to be 85. So people don't get diagnosed early. So in this study, we look at the time of diagnosis, which is the vertical line here. These are months before months after. And we're looking at the frequency of different behavioral symptoms in Alzheimer's disease. And again, you want to focus on a couple of things. You want to focus on, this is low level agitation or irritability. This is higher level, this is more moderate agitation, 80%, 80%. And this has been confirmed by other studies, not just our autopsy study, and about 40% in the later stages, more overtly aggressive behaviors. So this is a behavioral problem that is going to impact pretty much every patient with dementia, with Alzheimer's disease, whether they're at home, whether they're in the nursing home or somewhere in between and assisted living or memory care, which I'm sure you're all seeing, I can tell you in St. Louis and in our part of the Midwest, it's everywhere. New, more and more memory care assisted living units are popping up to take care of this patient population that the family can no longer take care of. Now why can the family no longer take care of them? Because of behavioral problems. So behavioral problems, particularly 2 stand out, agitation and psychosis are really the 2 most common behavioral symptoms that result in placement, either in assisted living or memory care or in nursing homes throughout the United States. So the loving family that's taking care of mom or grandma or the individual taking care of their aging spouse, their husband or their wife, usually their wife, women are more commonly seen, they're able to deal with all kinds of things. In the old days, the leading cause of institutionalization, believe it or not, was incontinence, urinary incontinence, particularly bowel incontinence. Now we have really good products to deal with those things. And people can get a little bit of help, hygiene help, that is no longer a leading reason for institutionalization. The leading reason, the number one reason is behavioral problems, particularly agitation and psychosis. So whatever we can do to help with those behaviors enables the family to keep their mom or dad or their spouse at home longer, which obviously is a great benefit to our healthcare economy. The other, by the way, huge reason for institutionalization, I don't want to not mention this, is false. Oh, at the point to the back. Oh, not so that's towards the that makes sense because the projector is back there. Thank you. All right. Well, all right, let's move on. So what do we do currently? I think Sheldon showed you what happens currently with patients with schizophrenia, patients with bipolar disorder. What do health care providers recommend for agitation in Alzheimer's disease or in the broad spectrum of dementia, which would include all the other dementia that we talked about earlier. So number 1, nothing is FDA approved. That's important to keep in mind. So everything that physicians and healthcare providers are recommending is basically off label for agitation and any of the symptoms of Alzheimer's disease or dementia. And similar to what you mentioned, Sheldon, is happening with the schizophrenia and bipolar patients, the same two categories of medications are being utilized, both acutely, whether it's in the emergency room, acutely in the nursing home or memory care, acutely at home, there are 2 categories of drugs. But the big difference in this population versus the population that Doctor. Presskorn talked about is, here we're looking at frail older people who have multiple comorbidities. They're not just on 1 or 2 medications. On average, they're on 5 or 7 or more medications, which they need. They have their blood pressure medicine. They have their arthritis medicine. They have their diabetes medicine. They have their hyperlipidemia, their cholesterol lowering medicine. Sometimes they're on too many medications and we begin deprescribing, which often helps. But this is a frail population that doesn't do well with the two options that are currently being utilized. So for example, I gave you some names of the antipsychotics. These are the newer antipsychotics, so called atypical. We still see the use of older drugs that are even more dangerous in this patient population like haloperidol. There's a specific black box warning on the labeling of all of these so called atypical or newer antipsychotics, specifically in this patient population. It's relative specifically to dementia patients that there's increased risk of mortality. It's one thing we don't want to mess with is mortality. We don't want to kill people, God forbid. But again, there's an increased risk of mortality, usually due to cardiovascular events that these drugs can precipitate, heart attacks and strokes. So that's obviously a major problem. Another major problem, and I think, Sheldon, you pointed this out, even in the older patient is these drugs take time to work, take time to kick in. They don't work immediately. And if you have someone that's very agitated, you might want something that works more quickly. The other group you also heard about are the Benzodiazepines. In the old days, these were the Valium and Librium drugs. The new versions of Valium and Librium are basically Xanax and Ativan and Klonopin or clonazepam. These drugs not only take time to kick in, but they can be particularly dangerous in an 85 year old, because they make confusion worse. And then the really big risk is they impair balance and increase the risk of falls. And you remember just in the previous slide that I told you that falls are a huge reason why people get institutionalized. My family has finally decided to move mom from her independent living, from the assisted living to the nursing home, because they now can no longer guarantee her safety. So safety is a huge thing. Number one reason overall for ending up in a nursing home is in fact false. And again, they take time to kick in. What about this new agent? Again, if the profile is, as Sheldon, as you pointed out, we have a drug that doesn't have the liabilities of the current therapies, which are again off label, the antipsychotics and the Benzodiazepines. And they indeed have benefits in this vulnerable population by not sedating, which also increases the risk of falls, by not making the person more confused, not affecting balance and confusion and so on, but having a positive calming effect. So with that, I'm going to finish and thank you all for your attention. I'll be happy to have questions later. Thank you. Many of you know that BioCell Therapeutics is a company that exists in Connecticut and specifically in New Haven, Connecticut. And that location has been very beneficial to us specifically because we get to tap into the knowledge base and the resources of Yale University, and in particular, Yale University Psychiatry, with John Crystal and his entire group. And as many Petrakis is one of those people who works actually in the VA under the auspices of Yale. So let me introduce as many who's going to provide an overview of acute agitation as relates to opioid withdrawal symptoms. Doctor. Petrakis is a professor of psychiatry at Yale University School of Medicine and Director of the Mental Health Service Line at the VA Connecticut Health Care System. Doctor. Petrakis is also the Director of the Addiction Psychiatry Residency at Yale. Her research interests are predominantly 2 fold: 1, finding appropriate treatments for the dually diagnosed individual and 2, understanding neurobiological mechanisms underlying alcohol dependency. So with that, I'll introduce Doctor. Petrakis. Great. So I'm going to change gears a little bit here and we're going to talk about opioid withdrawal and the opioid epidemic. And that's where I'm actually going to start. So as you all know, if you've read the paper at all in the last few years, we're in the middle of an opioid epidemic here in the U. S. This is an opioid crisis that's a public health crisis that's affected our country for several years, and it's really all over the news. So just to give you some facts to put it in perspective, it's estimated that 12,000,000 Americans use prescription opioids non medically. In other words, they're abusing them, they're addicted or in one of those categories. 1,900,000 people are addicted to prescription opioids and another 600,000 are addicted to heroin. It's a huge economic burden on the U. S. Where the CDC estimates that it's a $79,000,000,000 a year problem. But I think the reason that it really has captured the attention is because of the dramatic and tragic deaths that have occurred in response to the opioid epidemic. And what happens often is it's a young, otherwise healthy person who either accidentally or whatever overdoses on opioids, and it's just devastating to the family, obviously. So it's been estimated, I missed a 0 here, 700,000 Americans have died of opioid overdoses from 99 to 2017. That's 12 times the number of Americans who have died in the Vietnam War. It's estimated that 130 Americans die every day of an opioid overdose. But it's not just the overdose and those consequences. There have been medical consequences as well. So there's been an uptick in new incidents of HIV and hepatitis C. And that also got some news attention. There was recently an outbreak in, I think it was in Indiana, circumscribed, but still this is incidents, new episodes that occur above what you would expect from what happens to the normal population. There are also some interesting and tragic social consequences. So when you have youngish adults die suddenly, what has done is left some children without parents. So there was a article recently about the number of children in foster care due to the opioid epidemic. So this has social, medical and other consequences. So, yes, go louder. Oh, I'm not loud enough. Yes. Can you hear me better now? Yes. Okay. Sorry. So this is just a visual representation. And if you think about what happened with the opioid epidemic, this is opioid deaths, but it does highlight something that I wanted to mention here. So first, there were prescription opioids and you probably have all heard that there were there was an overprescribing of accidental deaths. And as people became aware of that and did things physician education, decreasing the number of prescriptions that could be given, The deaths plateaued, but in its stead, you see this uptick in deaths from heroin. And if you talk to patients, sometimes they will tell you that they couldn't get their prescription opioids. They actually turned to the street. They got heroin, which unfortunately, at the same time as all this was happening, became very available and cheap. And so that was an uptick. Now that has plateaued, but unfortunately, that's been overtaken by the most recent problem, which is an increase in synthetic opioids like Fentanyl. And again, you hear about this in the news as well. And they are very powerful. If you look at it, I saw an interesting slide that showed how much heroin you need to overdose and how much fentanyl you need to overdose, and it's very different quantity. And if you're not sure what you're doing, you don't know what's in it, it's very easy to accidentally overdose and you see this huge uptick in deaths. So there's a spectrum. People are prescribed opioids for legitimate pain issues. Sometimes they misuse them. They can become physiologically dependent. And then some people end up having what we call an opiate use disorder, which is an addictive disorder. And this is the definition based on the Diagnostic and Statistical Manual, which is what we psychiatrists use to diagnose and to communicate with each other. So this is a behavioral disorder. It's not just a physiologic dependent. This is a disorder where people are using opioids despite the medical, psychological and social consequences of use. And so in order to be diagnosed with this, you need several of these symptoms or events. So here, people are taking more than they intended. They try to cut back and they can't. They spend a lot of time obtaining, using or recovering from opioids. They failed to fulfill their obligations. They give up activities because of opioids. They continue to use despite medical consequences, physical hazards, psychological problems. Now tolerance and withdrawal are things that happen with opioids. So if you start taking, if you're prescribed an opioid, you take it regularly, eventually it's not going to work at the same dose, you need to increase the dose. This is a physiologic phenomenon and can happen to people who are prescribed them legitimately and taking them the way they're supposed to. So it's not necessarily a symptom of addiction, especially when you're talking about prescribed opioids. So in order to meet criteria to have an addiction, you need these other things to be present before you actually make that diagnosis. So there's this continuum, as I mentioned, people are prescribed opioids legitimately, they may misuse them, they may abuse them, and then they some of them become dependent and have an opiate use disorder. So there are treatments to treat opiate use disorder, and I just want to mention what they are. So it's sort of the context of treatment here. So the first is to use methadone. And methadone is a full on opioid, but it is limited in how it can be prescribed. You cannot just get this at your doctor's office for addiction. You can only be treated with methadone for an addiction if you're in a federally licensed facility. So it is not available to patients uniformly across the U. S. There are some places that have these programs and some that do not. The next is buprenorphine or Suboxone and some of you may have heard of that and there's a lot of emphasis on the use of Suboxone. So this has properties that are opioid like, but they're limited and at higher doses, it's more like an opioid antagonist or blocker. So it can be safely prescribed and there's emphasis on getting this out to people through regular physician offices. Now you can't not just anybody can prescribe it. You do need to have this added training. It's an 8 hour course and to have a special DEA license to prescribe, but you don't need to be in a federally qualified some kind of a federally regulated facility like methadone. And then the final is naltrexone, which is an opioid antagonist, which blocks the effect of opioids. And that's available either orally or with an injection. Orally, it really has not been found to be very effective for opioid use disorder except in very certain circumstances because people don't take it. But VIVITROL or the long acting injectable naltrexone is. And there was a recent two studies that showed some equivalence between buprenorphine and naltrexone for opioid use disorder. Okay. So moving on to opiate withdrawal. So opiate withdrawal give them an opioid blocking medication, then you precipitate withdrawal. And withdrawal is these symptoms essentially. It's a very well documented phenomenon. It's been shown. You can do it to animals. You can see it in humans. And these are the symptoms that people have: nausea or vomiting, you get dilated pupils, sweating, goose flesh, muscle aches, runny nose, diarrhea, fever, yawning and insomnia. But I think what I want to really emphasize is this intense state of unease or distress. It really makes people feel terrible. And they complain about it and it makes them agitated and upset. And patients will say that even patients that want to get off their opioid medication, they will say, I just don't want to stop this because I just never want to feel like that again. It can also dissuade people from seeking treatment for opioid use disorder. So it's a serious problem and sometimes it's the first foray of someone who's trying to get off their medications into some kind of treatment. So how do you manage opioid withdrawal? Well, there's several this is theoretical several ways to do it. You can slow taper whatever medications people are taking. I mean, you can do that for any addictive medication, you just slowly decrease it. But it takes time and there's no guarantee that people won't have some symptoms. You can substitute a longer acting medication in taper. So the 2 that are most commonly used are methadone and buprenorphine, but these also take time. And again, no guarantee that there aren't going to be symptoms. But the last is to treat the underlying neurobiology. And I'm actually glad my colleague mentioned the locus coeruleus and gave you an anatomy lesson there, so I'm not going to do it. But basically, just like in the disorders he describes, people who are opiate dependent, who stop their opiate use have an increase in noradrenergic function. And here in the locus coeruleus, you see overactivity that happens there. And this was this has led to treatments for opioid withdrawal that if you know that this is what's happening, if you dampen that down, you can then treat opioid withdrawal. So again, that is the mainstay of treatment for opioid withdrawal or the alpha-two adrenergic agonists. This has been for years and the one that's most classically used is clonidine. So clonidine is an antihypertensive or a blood pressure medication that decreases blood pressure and it's been used in opioid withdrawal. It is not FDA approved, however, it's been used off label for many years. And one of the biggest problems with clonidine is the hypotension or blood pressure drop that occurs when you're using it because it is a blood pressure medication. There is also another medication, lifexidine, which was just recently approved by the FDA in 2018. It is also an alpha-two adrenergic agonist like clonidine. The data comparing the 2 suggests that they have similar efficacy. They work equally well, but clonidine causes more hypotension or decreased blood pressure, which is not really something you want in this case. Now the way you do opiate withdrawal is one of 2 ways. You either just wait until someone's taking their opiates or heroin or whatever they're on, they stop, they develop these symptoms and you treat them. Another way to do it though is to add an opioid antagonist like naltrexone, which blocks opiates that precipitates withdrawal and then you treat that. Why would you do that? Well, it shortens the time that someone is in opioid withdrawal, but it can make patients feel crummy because you are actually precipitating the opioid withdrawal. Now the clonidine or what these agents don't treat all the symptoms. So often you do use some adjunctive medications like sleep aids or something for the muscle pains or for nausea. So at times when patients are going through opioid withdrawal, you do need to treat with multiple medications. Okay. So I just wanted to put it all together and say, so when are you going to treat opioid withdrawal? Because there are cases where you may not treat it. And I'll just put those and we can dispense with those. So patients who are coming in who have an opiate use disorder and are going to go on to either methadone or buprenorphine may not need to go through withdrawal. You may be able to treat them and they go for their maintenance treatment and that's it. But there are times when you do want to treat opiate withdrawal and I just want to be clear when those are. So first of all, for people who do not have opiate use disorder, but have a pain, but are addicted, perhaps physiologically addicted for pain or other reasons, they may be getting off because pain the opioids might actually be exacerbating their pain. So there's this phenomenon called hyperalgesia, which is being studied more now where people who are on chronic opioids for a long time, it might actually make their pain worse. They become more sensitive to pain is one way to think about it. So for those patients, they may really need to get off their pain medication and find alternatives for treatment. There are people who cannot tolerate the side effects, for example, of the pain medications or there may be patients who have an episode of pain become physiologically addicted, but now it's time to get them off. So for them, you may need to treat their opioid withdrawal. Now people have an opiate use disorder, there are instances when you do want to treat them and you need to treat their opioid withdrawal. Opioid withdrawal. So one is patient choice. Even if you think they be on buprenorphine or methadone, they want to be drug free, they are going to choose to get off their opiates. And so that's something that you might need to do. There are patients who are court ordered to go to, to be off opiates or perhaps they're going to jail and there is no opiate substitution there, so they need to be off their opiates. They're also otherwise mandated treatment. So healthcare professionals like physicians who become addicted to opioids and it does happen. If they get off of them, they are not going to be going on Methadone or buprenorphine, they're going to be going on naltrexone or be drug free and being monitored. So for those patients. There's also emergency management. When people overdose on opiates and they're brought to the emergency room, the way you reverse the opioid overdose is to give them an opiate blocker like naloxone. So they come in, they're obtunded, you give them the shot, they wake up, it reverses the opioid overdose, that's great, but they're often very agitated and upset because now they're in full blown withdrawal. So for these patients, they need to also be treated. And again, remember, this may be their introduction to treatment, and you don't want that to be a terrible experience because you're hoping to engage them in treatment and not have them just turn around and go back and use opiates. This is a big issue here, treating with I'm naltrexone, which is one of the 3 medications that is recommended in the treatment of opiate use disorder. You can't get on naltrexone if you're still taking the opiates. You have to be completely detoxed before you can start this. And so there's a lot of interest in figuring out how to do this smoothly, how to do this perhaps in an outpatient basis, so you don't have to be admitted to the hospital. And you have to really be off the opiates completely before you can start naltrexone. And then this is also another big area that's just being examined now. So what about all these patients that we put on buprenorphine or methadone? They're not going to they don't many of them don't want to stay on this medication for their whole life. When do they come off? When is it how do they get off? Do they transition to VIVITROL? That is something that is just currently being really explored. There's several studies that are being funded by NIDA to evaluate this because the guidelines now for people who are on buprenorphine or methadone are really unclear about how long somebody should stay. So this is a new sort of area that I think is very important. So that's it, except for that I did have a few, if anybody is interested in more readings. These are some really nice reviews, especially this one about opiate withdrawal. Thanks. So our last K is Doctor. Maurizio Fava, who will be presenting on hyperactive delirium and its relation to acute agitation. Doctor. Faber serves as the Director of Division of Clinical Research, Executive Vice Chair of the Department of Psychiatry and Executive Director of Massachusetts General Hospital Clinical Trials Network and Institute, the CTNI, Institute. He founded and served as the Director of the Hospital's Depression Clinic, Clinical and Research Program, the DCRP, of the most highly regarded depression programs in the country. Doctor. Favre is a world leader in the field of depression. He served as a principal or co principal investigator in numerous studies, most notably the co principal of the investigator of STAR*D, the largest research study ever conducted in the area of depression. So, Mauricio. Thank you. Good morning. It's a pleasure for me to be here today. In terms of disclosures, I am a consultant to BioXcel. However, I do all my consulting through the hospital. So I don't receive personally directly or indirectly any honorarium and I decline any transfer of value. That's why I brought my own snacks and water because I don't want to receive anything from the companies I consult to on behalf of MGH. In terms of delirium, this is an area that is kind of very important from my perspective. Delirium is kind of a condition in which there is an acute and reversible disorder of attention and cognition. The patients look disoriented, it's organized and you have a clear disruption on the sleep wake cycle. We typically characterize delirium in kind of in 3 ways. You have the hyperactive and agitated delirium where the patient gets kind of restless and agitated and may get violent or they pool the IVs. You can have a more lethargic or hypoactive patient with delirium that is confused, but basically doing very little. And then there are patients who have kind of a combination of a mixed state of hyperactivity and lethargy. Now delirium in the ICU is in intensive care units is very important because if you develop it, you have an increased morbidity and mortality. You have a prolonged stay in the ICU. And the study that was conducted in Australia on a 185 patients, it was a multi center study in 6 ICUs. They screened patients for delirium and they found that almost 45% of the patients developed it during the ICU. And I've seen this over and over the situation of intensive care, sensory kind of deprivation, many people become delirious in those settings. Another common cause for delirium is postoperatively. Now, very sobering fact is that 40% of inpatient surgeons in the United States outperform in people 65 years and older. And postoperative delirium is the most common study that was actually published a couple of years ago by Moscow with some colleagues looked at 172 patients who underwent elective operations with admissions and found once again 44% rate of delirium. Now you have to realize that in the same study when they did the follow-up, the mortality was 59% in those with delirium versus 13% in those without. So developing delirium either post operative in the ICU is really a cause for increased morbidity and mortality. Now you're going to say, well, don't we shouldn't worry about delirium because we got all these tools, antipsychotic drugs and a great study in the individual medicine last year kind of at least made us feel foolish because as you know, we've always used IV haloperidol, been big proponents. So it turns out that in this study that was published, as I mentioned, in the December issued in the New Zealand Medicine, they compare say, prasadone, an atypical antipsychotic or geodone with haloperidone or halo, kind of an old typical antipsychotic or placebo. And when you look at the days alive without a delirium or coma, there is pretty much no difference. If you look at days with delirium, this is placebo, alperidone, zeprazodone, no difference. And so it was a discouraging study. But in some ways, it suggests that we need to do better if we want to prevent and treat delirium in our patients. Now, interestingly, we have very robust data. In fact, we at Mass General, we do a fair amount of use of Dex for delirium, IV Dex based on a very important study from The Lancet 2016 that showed this is placebo and these are rates of delirium and this is dex and you can see that on the after surgery you have a marked reduction, significant reduction of delirium from day 1 to day 3 using Dex. In another study that was published by Kim and colleagues this year, last month, they looked at the Ryker sedation vegetation scale after extubation and looking at DEX added to an anesthetic sevofluren and sevofl alone had a shift towards more agitation than when it was used with Dex. So in my mind, we have compelling evidence that Dex can treat delirium, can potentially prevent agitation or delirium postoperatively or post estubation. And the interesting thing, last year, there was a terrific paper in Nature that showed that Dex has a protective effect against traumatic brain injury and damages of anoxy and so forth. So and a few years ago, a study looked at in laparoscopic cholesteatctomy patients, if you were given placebo decks, you have fewer cognitive impairment following the surgery, which was laparoscopic if you got Dex than if you got placebo. So for all these reasons, and this is a very recent meta analysis by ENG and colleagues of Dex in intensive care patients. And you can see that the bottom line is that you have an odds ratio of 0.36 with Dex versus placebo, which is really, really robust. And so in my mind, it's kind of the potential use of Dex as a prevention of delirium or treatment of delirium with the neuroprotective effects of Dex, which may reduce the impact, the negative impact of surgeries and anesthesia on the brain seems like a low hanging fruit. Thank you. So thank you, Maurizio, and thanks to all the KOLs for their insights on agitation as it relates to each of their neuropsychiatric specialties. They'll return in a few minutes during the KOL panel where you can ask questions and they'll address them. Right now, I'd like to introduce Doctor. Rob Reisinger. He's our VP of Clinical Development and is the Development Lead for BXCL501, who will discuss the summary of our clinical results and provide overview of where we're going in our registration trial. So Rob? Thank you. All right. Thank you for being here and participating in this. I have some very exciting results to describe. We announced this in a press release earlier this week on Monday. This is our 1st in human study with the sublingual film, BXCL501. The study was a double blind, placebo controlled, single ascending dose trial. We were testing 3 doses of dexmedetomidine 10, 20 40 micrograms. It was done at a single site, and we studied healthy volunteers in the range of 18 to 65. In fact, we had almost a 50% distribution of females to males. So, it was quite representative. Total number of patients, 42 patients. Each dose group was randomized 2 to 1, active to placebo. And our primary objective was to determine the PK, safety, bioavailability and of course, tolerability. So with that all right, it's working. Let me describe the pharmacokinetic results. It rapidly the BXCL501 film rapidly delivered to the targeted exposures, which were consistent with therapeutic responses we saw in agitated patients with schizophrenia when they were exposed to IV dexmedetomidine. I'll review that data in a moment. You've already seen a slide presented by Doctor. Presskorn. Note that this dotted line represents the lowest concentration, which was effective in the agitated patients with schizophrenia who responded to IV dexmedetomidine. The range of BXCL501 doses produced exposures, which were in fact overlapping with the range of exposures that we saw that resulted in a calming effect in the patient population as measured by the PEC score. The exposures were rapidly achieved. You see on the left hand side here, they were rapidly achieved by each of the doses 10, 20 and 40 microgram dose strength. And the PK was in fact predictable, was dose proportionate. And that enables us to select doses for future development. Further, the pharmacodynamic effects that we found lasted about 4 to 6 hours, and we believe this is an optimal treatment duration for agitation in particular. So next, let me describe the safety and tolerability findings from the first in human study. We found that dosing with DXCL was safe and well tolerated across the range of tested doses. There were no serious adverse events. The severity of adverse events was mild to moderate, meaning grade 2 or below. All adverse events were transient. They required no intervention and completely resolved. Most common adverse event reported was drowsiness, and the rate of drowsiness in each treatment group was similar to that reported by placebo group. The cardiovascular changes were not clinically meaningful. Further, we saw no clear sedative effects in comparison with placebo. A maximum tolerated dose was not achieved. The safety profile between the sublingual film and IV dex metatomidine when we were testing that in separate studies is consistent. And I'm going to review that in a moment. From these results and the PK observations, we're confidently advancing clinical development to dose agitation in patients with BXCL501. So before I describe the development plans, let me share the context as to why we're so excited about these results. To develop rapid proof of concept in agitation, we generated IV exposures across 4 different diseases. We conducted studies in 3 diseases and the bottom left in green was an independently published study. In schizophrenia, we saw a 90% response rate in terms of reduction in agitation using the PAC or PANSS excitatory component score. We saw this without excessive sedation as measured by the RAS, the Richmond agitation and sedation scale. Recall that the PEC is an FDA agreed upon registration endpoint for the indication of the treatment of agitation. In dementia, we saw a 70% response. In opioid withdrawal, we saw 100% response. And in a separate published study of agitated delirium, there was a 100% response. The pharmacokinetics and safety profile from these three studies in blue are remarkably consistent across the disease populations and with our sublingual film now that I just presented. So let me further detail the proof of concept study completed in agitated patients with schizophrenia. Doctor. Presscoran presented some of this data. Let me present the exact same data now. In our IV proof of concept studies, agitated patients with schizophrenia demonstrated a clinically significant reduction in PEC scores. They had exposures that were consistent with those that we observed in our film formulation. In the proof of concept study, the PEC scores were reduced before we saw evidence of rising levels of sedation. Let me just say that this degree of calming is robust. It's not just a few points on the scale, although it is, it's actually what clinicians think of as a therapeutic response. This is why it's a regulatory endpoint. So, when we were developing the film, we're targeting exposures that produce this robust reduction in agitation in patients with schizophrenia. The film achieves the exposures that equate with clinical PEC reduction in agitated schizophrenic patients, And that is why we're confident that the film can provide exposures that are potentially therapeutic in the populations of patients that we intend to test. So most reassuringly, I think, the PK and safety profile has been consistent across schizophrenia, dementia, opioid withdrawal. So let me provide you with a little bit more context regarding the levels of exposure that were achieved with BXCL501 in relationship with the labeled use of Precidex as an IV sedative anesthetic. PRECIDEX has a very impressive volume of safety data. It's been given and prescribed to more than 10,000,000 patients. There have been more than 120 published studies, some of which are reviewed today. Early in development, we saw levels of exposure that were 10 fold lower than the IV indicated use that resulted in calming effects without sedation in preclinical models. Since then, moving into the clinic, we've been systematically flushing out clinical data to derisk development and demonstrate a broad therapeutic index. There have been no surprises. We've been providing doses. We've been testing this in 42 patients now in this lower exposure range. And we believe that the lower exposures provide a benefit risk ratio that improves. In proof of concept studies, IV Dex in humans gave us exposures that were up to 4 fold greater. And these were well tolerated in agitated patients with schizophrenia. So, this data provides us with great confidence in advancing BXCL501 to test the safety and efficacy across a broad spectrum of illnesses. So, let me describe now the path to our first registration. This is the development plan for acute agitation associated with schizophrenia and bipolar disorder. This is a broad high level overview. We have a Phase 2 study in a total of about 200 agitated patients with schizophrenia, which we'll initiate soon. There's a 2 part study. The first half will dial in the doses and the second half allows us to characterize efficacy. Following this, we'll initiate 2 Phase 3 trials for registration later this year for a total of about 700 agitated patients, 1 in schizophrenia, 1 in bipolar disorder. These trials use the same endpoints and designs as previously successful registration studies. And we expect the registration trials to complete in the first half of twenty twenty, and that enables an NDA filing in the second half of twenty twenty. All right. So let me outline the Phase II designs. This is designed to derisk our registration trials. In this 2 part study, the first half will dial in the doses, while the second half will allow us to characterize the efficacy in terms of calming as measured by the change from baseline and PEC total score to 2 hours. The first half confirms effective doses, the range of dosing and the tolerability. 2nd stage characterizes variability in terms of response to a specific dose and that is critical to powering a Phase 3 pivotal trial. At the conclusion of stage 1, we expect to have at least 2 effective doses, which we label here as a lower and higher dose. The designs and endpoints are comparable to other agents, which achieved regulatory success. We've considered multiple options and believe this plan robustly increases the potential probability of success in separating from placebo in the Phase 3 in order to gain regulatory approval. We believe the Phase 2 trial is the most capital efficient manner to potentially derisk development without impacting timelines. These are relatively rapid studies to enroll. We outlined our Phase III registration trial I'm sorry, trials. We will have 2 registration trials for the same indication. We will have one trial for the agitation associated with schizophrenia and another trial for agitation associated with bipolar disorder. These will be running concurrently in parallel. This is designed very similar to the 2nd stage of the Phase II study. Patients are randomized 1 to 1 to 1, placebo, lower dose, higher dose. The inclusion criteria will be a PEC total score of greater than or equal to 14, and the primary endpoint will be a change from the baseline in the total score at 2 hours. The number of per trial will be in the range of 3 to 3 50 patients. The design is quite similar to previously successful global trials and will be very similar to the 2nd stage of Stage II. Like the Phase II trial, these trials are generally rapid to enroll. These patients are found commonly and that's why it's so easy and rapid to enroll. We expect to initiate these trials in the Q4 of 2019, and we mean to take advantage of operational efficiencies in conducting 2 trials in parallel. So we expect the data readout in the first half of twenty twenty. So as you heard from our panel of experts, we have multiple potential therapeutic indications. So, let me place these in the context of our plans for our first NDA for the indication of the treatment of acute agitation associated with schizophrenia or bipolar disorder. We will initiate the Phase 2 trial in the first half of twenty nineteen. These are short trials to execute. We expect rapid enrollment, principally, again, because agitation is a commonly encountered condition. We expect to have data readout in the 3rd quarter. That enables us to initiate our Phase 3 trial in the Q4 of 2019. Data from the global Phase 3 will read out in the first half of twenty twenty. And this data enables filing our NDA in the second half of twenty twenty. And then, we believe a commercial launch would ensue in 2021. In parallel, we've staggered development plans in agitated dementia, opioid withdrawal and delirium. These plans will be rolled out throughout 2019 all the way through 2020. And as part of the planning process, we consult with our expert advisors to systematically examine, evaluate and derisk the development in order to achieve technical and regulatory success. Our development plan for agitation associated with dementia will be rolled out likely first in the later half of this year. All right. So with that, let me turn this back over to Frank, who will describe our agitation franchise. Okay, Rob. Thank you very much. Thank you. Good job. So just two other points that I want to make, and then we can take a break before we have the KOL panel. We view DEX as a significant opportunity, obviously. And we our first attempt really is to look at DEX in the context of acute treatment of agitation. But there's a lot of other and that's really for mild to moderate, but there's a lot of other things that could potentially that this drug could be potentially used for. So the first two opportunities are what we're pursuing now, which is the mild to moderate in psychiatric disease and the effect of the drug in terms of acute treatment in these other indications, but we're also there's still the problem with severe agitation and the types of drugs that are used. And we think that potentially DEX could play a role in this area as well. And what we've been doing is we've been experimenting with some combination treatments with DEX. In other words, trying to take advantage of a synergistic pharmacological effect where you can lower the actual dose of both to get a basically anti agitation effect. So this is one thing that we are pursuing right now. And when we have more information on that, we will show you what we have at the proper times. But the other is the possibility because the drug is and really seems to work well, we think will work well as an acute treatment, the possibility to tie this to some kind of digital integration. So what do I mean by that? Well, what we're doing right now is we are now taking patients who are already agitated or on their way to being from mild to moderate to severe agitation in treating those patients. The question is, can you, by utilizing some digital software and digital hardware, can you come up with a process where you can determine whether or not these whether these patients are on their way to becoming agitated? Because I think the beauty of DEX is if it's well tolerated, which we think it is, and particularly because it has the low dose phenomenon, there's a chance that we could, if this could be determined, that we could abort potential agitated events from occurring, not just treat, okay? So one of the things that we're pursuing here is to see utilizing, understanding the pharmacology of the drug, the sympathetic nervous system, all those things rolled in. Is there a way to actually determine this phenomenon with proprietary algorithms, utilizing our capabilities in AI, okay, to predict emergence and notify caregivers. So just thinking about it, putting in a simplistic way, thinking about a patient wearing something like this, particularly if you're thinking in the area of dementia, and the caregiver has the phone, and they all of a sudden get an alert that this patient is on its way to becoming agitated. And the idea is could giving a drug like dexmedetomidine prior to it stop the more advanced issues that occur with an agitation attack. So this is where we are right now. This is in development stage, we're thinking. But we believe that Dex offers us a really unique opportunity to marry with this type of science, the digital integration, okay? So I'm going to stop there. I want to thank you for your attention so far this morning. What we're going to do is we're going to take a 10 minute break. The restrooms are down the hall, okay? You can mingle for a while, and then we'll come back with the KOL panel. Thank you. It works. Hello, everyone. We're going to start the next agenda item now. If you can kindly take a seat. We'll do now is we are going to have our panel discussion. And just a note, Doctor. Fava has to get back to Boston. So what we're going to do is ask you to potentially focus your questions on delirium or any other questions that you have for Doctor. Faber to do it early so because he has to leave in about 20 minutes. I also want to take the opportunity this session is going to be moderated by Sumant Kalkarni, who is Biotech Research Analyst at Canaccord Genuity. Thanks. And thank you, everyone, for being here and tuning into the webcast. We do have a mic going around, so please feel free to raise your hands to ask a question. Don't be shy. Thank you also to the distinguished panelists here. I'm going to kick it off with one kind of big picture question. We've heard a lot about Y501 or DEX in its format that BioXcel is trying to commercialize eventually is good. But is there anything in Precidex as a molecule itself or this formulation that might want you to not make this not use this product in the patient indication that you might be going after? So we'll start. The main issue with the is that it can lower blood pressure and heart rate. So this is really a surgical drug for affecting surgical precision, pinpoint precision, in comparison to all the other drugs, which have targets, either targets that widely affect the brain like Benzodiazepines or multiple targets, this has one target. And that target is the locus coeruleus. And if you remember that the downward pathway controls blood pressure and respiratory drive, the upward is arousal. And so the key thing is to achieve a dose, which decreases arousal without affecting blood pressure and heart rate. And that was a key feature in the IV Dex studies that were done. And so that was really aimed at to determine the therapeutic index where you would have wide separation between an anti agitation effect and an effect on the cardiovascular system. Yes. Maybe I can add to that. So I referred a couple of times during my brief presentation to the 85 year old. We've kind of redefined what geriatrics is these days. We feel that people in their 60s 70s are in their middle years. And you really don't start taking geriatric until people hit the age of 80, particularly 85 plus. And we know that as you get into your 90 decade of life or beyond, the sensitivities as far as autonomic nervous system related issues such as blood pressure and heart rate and so on can also increase. So one of the issues which will be very important will be to determine the optimal dose for that vulnerable, more frail 85 year old who has Alzheimer's disease, who's agitated and maybe won't allow the family or the caregivers to give them a bath or a shower or to dress them or change their diaper or whatever without affecting those same parameters. And it may be that the dosing will be the ideal dose may be lower for that population versus the young robot, schizophrenic or bipolar And if I could go on, I would say that's also the logic behind the development plan in terms of starting first with schizophrenia and bipolar patients, gaining experience now through the Phase 2 and 3 studies and then looking at going into potentially more vulnerable populations. So all of that is really accumulating data to drive the design and the dosing of the next studies. And the other issue is really the fact that you can see, for example, in delirium, whether you can use Dex for the treatment of delirium, which may require probably higher doses or for the prevention of delirium, which may require lower doses. And that to me is a very, very appealing thing because if you think about it, the study suggests that the elderly 45% of people post operatively may have delirium if you can reduce the risk and the currency, if you prevent delirium, you're saving lives. And so the dosages may be even lower when it's used for prevention because you're targeting the local ceruleus, you're trying to diminish that hyper arousal and which can be so lethal in our patients. And those patients are also largely geriatric patients because advanced age is probably the 2nd number 2 risk factor for dulirium. Number 1, being preexisting cognitive impairment. You're looking at that same population. The other issue I wanted to add is the benefit of a compound that is not a knockout drug that doesn't cause too much sedation. Because sedation in my population, again, the 85 year old, is a huge risk factor for falls. And as you saw, falls not being able to guarantee safety are the number one risk factor for ending up in a long term care facility. Yes. So it's slightly different for opioid withdrawal because the medications that already exist have a similar mechanism of action. So it's not that this has a completely different mechanism. So, I think what would be important for opioid withdrawal is this is there, it offers a benefit. So, example, if it's more effective than clonidine or causes less hypotension, those are all things that would be really important in terms of using an opioid withdrawal. So I'll ask a couple of questions here to Doctor. Fava because, yes, Lee, but you mentioned that a large percentage of patients already experience selenium when they're in the ICU. So what prevents use of IV Dex because it should be relatively simple to use in that setting? What would make a sublingual formulation? No. In fact, at Mass General, we use significantly Dex in the ICU and postoperatively. However, in general, we see these are issues of implementation science, even though deaths has the most robust evidence in delirium, you still see hospitals continuing to use antipsychotics for delirium even though the new regional medicine showed that it really it's no better than placebo. So unfortunately, we tend to practice a little bit the same way we used to practice 20 years ago. But there's no reason right now not to use it. The question in my mind is because people would say, well, why not using Impressadix? Why do you need a normal formulation for delirium? I think that the idea is that psychologically, the idea of an IV intervention for prevention is not appealing to doctors. They don't like the idea of giving something IV for prevention. Oral for whatever reason, psychologically they say, okay, it. So I think that and particularly if we're using lower doses for provincial delirium, this could be in my mind a breakthrough clinically. And given you are so much in the known use of Dex, it doesn't take too much convincing for you, but what do you think needs to happen for wider practices to adopt dex? Well, I think that the we've seen that in all the areas you have to start educating. You have to start really elevating the practices and kind of the quality of care. Unfortunately, in delirium, I think this has been a neglected area. And I've seen over the years, whenever you have a new treatment and people get educated about the condition. How many hospitals really get very, very good education about treatments of delirium? We can really see a kind of a deployment of educational programs in this area to kind of raise the standards. And this was something that I was planning to ask last, but given you have limited time, I'm going to ask it upfront anyway. Payers and pricing are in the public eye for better or worse. How do you think that might influence the use of Dex in the ICU setting if there is a new branded product approved as a first one? Sure, sure. Well, I think that I don't know how people will react. But again, IV administration is more expensive than all. Oral, the level of monitoring that it requires. So I think that a cheaper IV versus a more expensive oral, at the end of the day, people may side with the more expensive oral because of the safety and the lesser need for a kind of vital size monitoring. Yes. And certainly in our situation, it requires an anesthesiologist to be present. So when you use IV Dex, so you're probably so what's your the trade off would be a reduction in professional fees versus the cost of the medication. So I think one could probably actually do an economic analysis of that. And I certainly think that adoption is not going to be problematic because there are many of these drugs that are available. They haven't been developed for this reason. We talked about clonidine. But the issue is having it in the right dose form and having it in a rapidly absorbable and predictable absorbable way. That's the difference. So I think doctors will not be particularly surprised or require a great deal of education about the mechanism and that these are useful, but rather understanding why this formulation, the science behind the delivery of the right dose will be the critical issue. Let me just add to that. We've been focusing on delirium in the ICU. The reality is, is that there's more delirium hospital on various wards where we get asked to consult on usually an older adult who is now acutely confused. Maybe they don't have an IV and obviously in the nursing home and outpatient settings and going to an IV preparation is not desirable. Having something oral is obviously much preferred even if it's at a greater cost, much better tolerance. In my agitated dementia type patients who also are at risk for delirium, they're going to pull the IV out. They're not going to you may have to strap it down. It's very complicated and just not practical. So the oral form, I think, has great potential. Where I really see a lot of potential and I haven't been aware of it until today as you brought it up is the prevention concept because we already know what the risk factors, who is the greatest risk for developing delirium. We know those factors. And if we can identify those people and treat them and prevent, wow, that would be amazing given the huge cost to our healthcare economy and quality of life for patients and caregivers of undiagnosed untreated delirium. Yes, that's a great point. And the studies are focused on delirium post operative in the ICU because they have the highest rates of delirium and it's easier to study them. But delirium happens throughout in patients, people who usually attract infections, they become delirious, elderly. So and they don't have IVs and they're so the access to an IV is not the same. That said, even in where you have the IV in and you could say, well, isn't that easier just to do it, I still think that the use for prevention will be much more acceptable in oral formulation. If you have any questions for Doctor. Babak, please raise your hands. I'll ask a general question now. I'll start with Doctor. Petrakis because we've seen Dex, we've seen the label for IV Dex. Now granted that could be a very different situation, but how do you see the potential for Dex to have any kind of drug drug interactions, especially given that patients in either the opioid use withdrawal indication or the others are already on various other clinical drugs. So I don't know, are you saying specifically about the IV formulation or just in general? No. In general, a formulation like this, how would that help for practice given Dex might interact with some of the drugs that are already being used? Right. So a lot of times, opioid withdrawal is actually occurring in people who are relatively younger and healthier. So I think these are less issues than it might be in the geriatric population, for example. And most of these patients, if they're on other medications, it may be adjunctive to treat the withdrawal, just to treat some of the symptoms. But in reality, they don't necessarily have to be on a number of other medications. They may be relatively healthy. They're taking opiates. They stop their opiates, they go through withdrawal. So I don't see the treatment as being particularly problematic in that setting. For Doctor. Prascon, you mentioned the vignettes there, which involve Lindt Bourbon. How would alcohol interactions and things like that? Any special studies that might need to be done there? Yes. Well, certainly, if you're dealing with alcoholism and you're dealing with delirium treatments, physicians are going to need to be cognizant of the fact that they may have volume depletion. They are in sympathetic overdrive. So, again, one would be cautious with regards to dosing and dose appropriately and look at vital signs, etcetera, when you do that. But that's nothing different than what happens today. When you're treating delirium patients and agitation patients who are generally uncooperative, what is their willingness to take an oral medication? Is that something that you plan for or have procedures and techniques to do? Again, once the patient is completely delirious and aggressive, it may be very hard at that point to have an oral administration. But as I mentioned, if you have a 50% risk of delirium postoperatively, you can give this drug to everybody surgery. And you have the cognitive protection that has been suggested by a number of studies. And you're reducing the incidence of delirium. So to me, you don't have to wait until the patient gets really hyperactively and aggressively delirious. You give it preemptively and you're preventing it. That's why to a certain extent we're probably going to see in the hyperactive really agitated delirious patients will see a combination of IV and oral therapy or I'm whatever parenteral when they're really, really agitated and delirious because they won't be cooperative enough to take something orally. But I would say for prevention, that's going to be very easy. Let me just add to that. And I agree with everything you said. So for acute treatment, whether you have agitation, irritability, agitation, mild to moderate, overtly aggressive behavior, whether it's due to the derium, whether it's in the context of the dementing disorders like Alzheimer's disease, the degree of the agitation, aggressivity and the acuity of it is going to determine whether you're able to get the patient to take something by mouth. So probably 80% or more of the patients will have mild to moderate either irritability or agitation and won't be overtly aggressive to the point where, as you pointed out, you may have to even get something intramuscularly like an injection. They may not even stand still for an IV, but that will be the relative minority, at least in the delirium slash dementia category that we would run into. I think the whole point is to catch this early. And as we sort of indicated in the slides, you start out grumpy, anxious, on edge, a little irritable, frequently at that point you actually want treatment. And the issue is having a treatment that is well tolerated and safe and doesn't cause side effects and does not behaviorally disinhibit the patient. I'm impressed by the fact that markets don't define drugs. Drugs define markets. And until you have a novel treatment, a treatment that does something existing existing treatments don't do, you don't really understand the size of the potential market. And I'll give you a simple example. With the introduction of Prozac and the subsequent SSRIs, the market of antidepressants went up in order of magnitude. That wasn't because the market didn't exist. It's because with the old drugs, they were so dangerous that you only gave it when you absolutely had to. With the new drugs, the danger of the disorder vastly outweighed the drug. I'll move on to a specific question on dementia here. Now this product, 501, is going to be a rescue treatment for the most part, but we are aware of other drugs in development for dementia related psychosis or treating agitation. How do you think your SKU treatment or the landscape for SKU treatment might change if other drugs are approved more as chronic treatment? Okay. So I was thinking of actually presenting the slide for you to show you what's in the pipeline as far as the treatment of agitation in dementia or in Alzheimer's disease. The drugs that is closest to approval is an antipsychotic. And it's in Phase III trials right now. And it does have unfortunately the same liabilities that all of the antipsychotics have, including the black box warning, which for many clinicians is a major deterrent for prescribing. Their Phase II data looks promising and looks positive. They're in the middle of a large multicenter Phase III trial. There have been a couple of other drugs in the pipeline that are not antipsychotic that unfortunately have failed recently. There's another very interesting compound that's also kind of number 2 behind the antipsychotic, which is a unique compound, but again, very different than this one, has much more of a sedating kind of posture. And then there are things that are really much farther back where there's no guarantees that they're going to pan out. So I think from a structural standpoint, a side effect or tolerability standpoint, the profile of this compound is different than anything that's in the pipeline. And I think meshes pretty well with what we get concerned about relative to our older dementia patients with agitation. This is not an antipsychotic. So I think we want to keep that in mind. And that's a plus because the antipsychotics have a lot of heavy duty baggage in this population. So I'm going to ask almost a pure investor type question to make our lives easier here from a modeling perspective. So if you go at each of these indications and you look at the patient profile here, how many times do you think an average patient might need to use this film in, let's say, the schizophrenia, bipolar disorder setting or dementia or in opioid use withdrawal in a given year, any averages or medians you might care to throw out there? I would say that it's quite variable. But I think that, again, it depends upon the efficacy and the safety and the tolerability of the drug. So for example, if you looked at a patient with Alzheimer's disease, I'm going a little off target, but what frequently leads to them not being able to stay at home is sundowning and agitation. And if you could administer this drug to aid the patient in not getting up and wandering, not get up and being frustrated, then you and irritable, then you prevent that person having to go into a nursing home. In the nursing home, again, they can be pacing, they can be in other ways agitated, etcetera. When they reach a level that the nursing home doesn't isn't able to manage them, then they go into a gero psych unit. So each one of these is an increase in cost. And so you could imagine a patient potentially needing a medication like this on a nightly basis. Again, this will vary depending upon the stage of the illness they're at. But so I can try to give you a partial answer because I think it's a great question. I don't think we really have all the data to fully answer that question. So it may be that this could be used as a PRM or as needed drug when the occasion arises, whether at home or in the long term care environment. Or it may be that we're going to learn from our studies that patients do better who maybe have more chronic administration, their quality of functioning improves and they're much more manageable. I think that's an important issue. We need still need more answers on that. So I think did you want to finish that? So I think the answer that is variable is true. I think unlike the other disorders, an opiate use disorder, what you would hope is that you detox someone once and then they go on to treatment and that would be the end of it. But of course, that's the ideal and very infrequently happens because opiate use disorder is a chronic relapsing disorder. So even for people who are, say, taking methadone or buprenorphine, the number of people who stay on the treatment in a year is less than 50%. So that means that they're out but using again and they're going to go through withdrawal again. In a year, I don't know how often it's going to be. The other thing that's happened now is that there's a big emphasis on prescribing NARCAN, which reverses opiate overdose, which people take in the field. That can precipitate withdrawal acutely out there. You don't really know how often that's happening because there's not good data on that. People are doing it at home. They're doing it with their friends, their family members. So but it is common that people will experience opioid withdrawal more than several times over the course of the year. Yes. And I would say the other thing is the company has data that the drug has preventive actions. This comes from preclinical rat data using an intruder mouse experiment in which you dose the animal knowing they will typically attack the intruder and actually demonstrate that pretreatment decreases the percentage of attacks. Now, that's difficult to do in humans until you have, so you're going to start with acute symptoms. But then as you get comfortable with the drug, it's conceivable that you could look at a prevention treatment. And Doctor. Prescott, you brought up an interesting point. You said potential nightly use. If you look at, again, the intravenous label that's out there for the approved Precidex, that is, I think, they use the word tolerance to dexmedetidine. Is there any potential to develop a tolerance for this drug if used in a different formulation? So you can develop tolerance to alpha-two drugs. And with chronic administration, with quanidine, for example, you can get rebound hypertension. I think the concept here is the drug would be used for a short period of time at night. The drug is relatively rapidly cleared. So you wouldn't be looking for sustained effects of the drug. And tolerance typically occurs when there is chronic blood levels of the drug resulting in a reregulation of receptors. So I think with the pulsatile effect, that will diminish that possibility. And then moving on to the setting of use. For the most part, again, this is probably going to be used where a care provider is present. What about the potential for a film of Dex to be allowed for at home use? And how do you see that evolving? Are there any roadblocks that you might see in getting that in the homes? Well, I think that will be a function again of having adequate safety data in sizable percentages of patients. It probably is not much different than taking a drug over the counter, where you develop enough history with the drug that you are able to then use it in less restrictive environments. So certainly, I think right now the plan is to look at it in carefully defined populations with acute levels of symptoms for the obvious reason that this is the initial entry into the market. And then if you look at the effects of the drug and safety profile, that will dictate the comfort level that the FDA would have with moving it to a less restrictive environment. I was going to say, in the patients that I deal with and working with them and their families and professional caregivers, they're used to giving patches, they're used to giving sublingual nitroglycerin, for example. So this is not something that's different. And again, if we have the safety and tolerability profile, something that actually could be advantageous in my population, a lot of whom dementia patients often have difficulty swallowing pills. They get stuck, they spit them out, various other things. So having a film that instantly kind of dissolves under the sun, patient can swallow it, they're getting the medication and it's easier to administer. So I think in many ways it could be attractive. On the opioid withdrawal side, clearly, this is not a new mechanism of action, as you mentioned. So what might you consider might be the biggest hook for the use of a film in that setting? So first of all, it's the action of the medication. So if it causes less like hypotension, for example, like Vinclodidine and more effective, that would all be a big sell. I mean, film is quite appealing in this population. So, the Suboxone or buprenorphine is that's the way it's given. It's in a film preparation. And if people feel nauseous, swallow pills, like you mentioned with the geriatric patients that might be a plus. IV is unlikely to be used in these settings. First of all, most people, they may not need it. 2nd of all, if you're talking about an IV drug user, they may have limited access to the vein. So a medication that can be administered in another route is a real plus. And DEXA is a very well characterized molecule given it's been out there for so long. Now if you had and there's definitely not going to be an advisory committee meeting here, but Doctor. Prasanna, you've been part of many. So if you had to look at what the FDA might do, assuming all the trials work as they're intended to and the drug is safe, efficacious and things like that. What do you think the FDA might if you had to nitpick, what do you think the FDA might pick on to not want to approve a product like this, if any? To not approve it? Yes. Is there anything that you see that the agency might raise its eyebrows on? Well, the agency is always looking at and I'm speaking having actually served on the psychopharmacology advisory committee and my comments on over the counter, I have actually served as an expert testifying to the over the counter committee so that I have some idea of what they look for. But all of drug approval is a balance of the efficacy of the drug in a given condition versus its safety and tolerability. And that's the bottom line. The reason why you have indications is to show that the drug has a effect size, a therapeutic benefit in a given population, and then you weigh that against the safety and tolerability of the drug. And that's what they're going to look for with this compound. Yes. I could maybe add that in dementia patients and Alzheimer's patients, the FDA has been relatively liberal in generalizing dementia as a whole rather than being specifically focused on one subtype of dementia like Alzheimer's versus vascular versus Lewy Body. And there are a whole range of different compounds that are in the pipeline that they've now approved the studies for. The bottom line will always be in a vulnerable population where these patients often can't even give informed consent, you have to have the family and the legal representative give informed consent, it's going to be safety and tolerability. And as long as you can show safety and tolerability and the drug is efficacious, I don't think there'll be any problem from the FDA. For opioid withdrawal, I don't know if this is an FDA issue or a marketing issue, but it would seem that if you distinguish it somehow from ophaxadine, that would be important point to at least be thinking of that. And if you look at Lofexidine, you have very serious adverse events percentage wise. So the other thing that the FDA looks at is what's the severity of the untreated illness. So the couching is the efficacy of the drug in the illness, the seriousness of the illness and then the safety and tolerability. And I think you can readily see that in the lifexidine package insert and where one considers the problem of the opiate epidemic. So about risk benefit ratio? So we have a good sense of what the competitive landscape is on the withdrawal symptom side. But if you look at agitation as such, there aren't really a whole lot of treatments out there. Doctor. Grossberg, you mentioned you might have had a pipeline slide. But are you aware of any other products that might go head to head versus a 501 film on the agitation side that might be making it to the market around the same time or a little after? That's hard to predict because I was on a recently on a safety monitoring committee, safety and efficacy monitoring committee for a compound that was already in Phase III where the interim analysis showed that it failed, it didn't work. You just never know. I think you have a compound here where we know that at least in certain populations, it does seem to work. We do have some relatively reassuring safety data, particularly if we can figure out the optimal dosing for the given population. So again, I can't be a soothsayer and tell you that there's anything that's quite like it. There is a compound which will probably get approved, but who knows, it could fail, which is a combination of dextromethorphan and clinidine, which has some similarities. But one of its liabilities may be sedation. So it is a real sedating compound, which does have antiagitant effects. So it's hard to predict. I think this is again different and unique and it could potentially have a role, but we'll see. And just delving a little bit into the data that BioXcel has on the product so far, we're heading into a Phase 2 here in the schizophrenia and bipolar disorder indication. But given what you've seen so far, what would you say would be the most impressive or not characteristics of the data that are out there that have been generated by the company on the 501 films specifically or in the bridging studies? Well, I've been involved in all the IV studies. And what's truly remarkable, and this is going to be presented at the American Society of Clinical Psychopharmacology next week, is how reproducible the data is from one population to another. The drug is very well behaved in terms of its predictability. And I think that to me is what's truly striking. There's a question in the audience. Yes. Scott Pachever from Barclays. I'm just wondering if you could give us a breakdown of your current mild to moderate patients that are on antipsychotics or benzos or others? And what percent you would switch to the 501 asset if it was approved? And maybe which patients would be least likely to switch? And then maybe as a follow-up, what the potential abuse potential is for patients and caregivers for this asset? Well, I think probably you're not necessarily looking at switching. There are plenty of people who are on antipsychotics medications because to treat their psychosis. Your situation is when they start to get agitated, when they start to get restless, some of which may be reducing the dose of those medicines. But I would say rather than necessarily switching, it is really using the drug as a PRN as needed basis for specific symptoms. And then I'm sorry, I didn't catch the last portion of your comment. Just thinking about the abuse potential of the asset of Yes. I don't know of any evidence for abuse potential of the drug that I'm aware of. It's not particularly rewarding. But on the other hand, humans are remarkably Actually, it was a bad because it hits your valves and it makes your heart flutter. So, it's I never there's always a possibility. I guess, we have a formulation question on peanut So, clearly, I mean, each of you have experience in a wide variety of indications, not just the ones that you were speaking on today. So if you have to look at other indications that a film like this might be useful for neuropsychiatric setting, what might those be? Yes. So I just I'm just thinking about this as you're asking. I think it's a really good question. So we've already discussed a broad array of potential indications. I think if the company would be very fortunate to have those indications approved by the FDA, you're going to be one of the larger pharma. But again, there may be other areas potentially depending on whether the compound has let's say anti anxiety effects. Maybe at particularly low doses, it might be able to be used for either acute treatment of anxiety or even longer term chronic treatment. We've only peripherally touched on alcohol. And one of the things I just wrote a piece in a national magazine that's gotten a lot of attention where I commented about the opioid epidemic and how as horrible of a problem as it is, nobody because of that is talking about alcoholism anymore, which is by far and away a magnitude greater problem for our society by in every way financial cost, emotional costs, families broken, suicide, you name it than the opioid epidemic is, but we're no longer talking about it. So if there's potential in the alcohol abuse area, again, I don't know that would be another huge opportunity. One other area as clonidine was looked at a little bit in post traumatic stress disorder that which is another disorder that has a lot of hyperactivity in the noradrenergic system. And the medications to treat PTSD are pretty lousy. And so I mean that's a huge issue. It's growing population, right? For dementia patients? I'm sorry, emergencies you're talking about? Yes. Yes. I mean, I think it can be. So we touched on this earlier that this may potentially be kind of a PRN drug, which can be used in acute situations. Where it may not be appropriate because of the sublingual film component would be the out of control aggressive patient where whom as Doctor. Fava mentioned, you may even have to give an intramuscular perhaps in the emergency room or wherever to get them to a point where they may be able to use a film like this. So I think it does have potential as an as needed drug for mild to moderate agitation in the dementia population. But some subsets of that, the overtly out of control patient at that point in time may not be a candidate. And as Among nurses and And ER doctors. As far as how they would use this versus what's already available off label? Okay. I'm not sure I fully understand that question. But I think that let's think about where the drug would be used. So it can be used in the outpatient setting where a family member might administer it under guidance from a physician similar to many other medications that they currently use. It might be used in an outpatient clinic setting, maybe used in the emergency room in all but the totally out of control patient. It may be used in the assisted living memory care scenario where these patients periodically with dementia do have these problems always under the prescribing of a physician, but may be administered by the nurse on the unit and the same thing in the nursing home. Advanced practice nurses, PAs would be able to prescribe this. So this would not be as far as I know, would not be a controlled substance. So they should be able to freely prescribe it without restriction. Now reimbursement, we haven't talked about that. Doctor. Prescott and I were talking earlier that there are some physicians for example and prescribers who are reluctant to prescribe anything that's not FDA approved. So they're reluctant to prescribe off label. And insurance companies, I've been told by our legal people have a legal right not to reimburse things that are also off label. Doctor. Prescott said, well, sometimes they don't want to reimburse even things that are on label. But that's true. But you have a much better case when something is on label and you can justify that that's the best medication for that patient in the office or in the nursing home. It's the safest where the basically the risk benefit ratio is the highest. So I think it's going to be widely prescribed by a range of health care providers and there should be no impediments. I think all of these things are really driven by the Phase 3 data and what's the therapeutic index. The wider that therapeutic index, the more you can see at home prescribing, you can see prescribing use I should say use at home, in nursing homes, etcetera. And I think physicians may I always say you're using an approved drug for an off label indication. But so we sometimes use quanidine in folks who have trouble falling asleep. That's not common, but we do. And this drug produces a sleep architecture rather comparable to normal sleep architecture. And one of the things that the locus Aureus does sometimes is to when it intrudes when you should be going to sleep, it keeps you awake. So, I'm always leery about going too far afield from what are the planned indications, because I think you have to do first things first. And that's certainly defining that therapeutic index. Hi. Edward Mark, HC Wainwright. Following up on that alcohol use disorder, wondering if this could be used for something like There is a huge graveyard of medications that have been tried for cocaine and methamphetamine. I mean, there's they've tried a lot of different agents. I mean, I suppose you could try years years of trying to find something that helps with those disorders has been pretty frustrating to say the least. That doesn't mean that it couldn't possibly be tried. I don't remember the literature on the quantity from TRY in this area. Maybe I don't know if they'll dig it out of don't know. I have to dig that out. I just know it's been an area of frustration. The issue is that when you go into withdrawal frequently, you activate the locus coeruleus. So it's a component of the agitation and sympathetic overdrive that you get with substance withdrawal, a variety of kinds. So you have really 3 phases of addiction. 1 is the binge intoxication. 2 is the adaptation and withdrawal phenomena and 3 is anticipatory. During the withdrawal, which actually is what drives principally addiction, part of the symptomatology arises from locus rueus overactivity. Now that doesn't mean the drugs will treat the addiction. It means they treat the symptoms from the withdrawal phenomenon. And then just on a broader level, I'm wondering what APIs might be used most strategically with 501. You talked about it being used individually in acute settings, but is there any sort of medications that patients might be on for more chronic level that would either not be used very well with 501 or would be most beneficial to be used with 501? I think you'd be careful about antihypertensive medications. And so for example, drugs that block Alpha-1 receptors cause orthostatic hypotension. And so that's working on a different adrenergic receptor, the Alpha-1. So I think, again, this would be where you begin accumulating data. Is that does that pose a problem? And so I think one I would think certainly in terms of things such as blood pressure medications, which ones are problematic if any. Yes. So I can add to that. So obviously blood pressure management is particularly important in older adults. A lot of times their fluid intake isn't very good. They might be have a tendency of dehydration. Even without antihypertensive blood pressure medications, they tend to have a lower baseline blood pressure, especially if they're not getting enough liquids. So anything that could potentially exacerbate that would be considered problematic and may affect dosing and utilization. There are some common off label drugs that are used in this population, in my population for mild to moderate, but more mild irritability. One that comes to mind that's used very commonly is an antidepressant called trazodone. And trazodone at high doses, which older people can't tolerate, is a good antidepressant. But it's way too sedating and drops blood pressure. But even at low doses, again, it can mildly lower blood pressure. And if it's combined with an agent like this, we'd have to be particularly cautious and maybe that you don't want to use that combination together. So, a lot will depend on what the patient's already on and what the profile of that compound is. We're almost out of time here. So, please have a question. We touched upon reimbursement a bit. But for a product like 501, especially if it's used in a care setting, do you think it would be reversed as a pharmacy benefit or a procedure benefit? And would that make any difference in potential to be used? I would think it'd be more of a pharmacy benefit, but that's not particularly my area of expertise. I don't know if you guys want to add it. Yes. Thank you. So first of all, I want to thank our distinguished panel for making the effort and answering all the questions about the program and for 501 to go in different directions. And I will remind everybody one statement that Peter always say is our company's strategy is to land and expand. So we want to land and want to get to the NDA as fast as possible with one indication so that we can get this drug approved. And that's the path we have chosen with schizophrenia and bipolar, our plan that Rob described today that we feel that the fastest path to get there because there is a regulatory precedence in terms of the clinical endpoint, which is reduction impact. At 2 hours, there is a FDA has already approved such drug. So that has as well as the drug has been reimbursed by the reimbursement agency. So we have some baseline there that like how you can get this candidate for acute treatment of agitation resulting from schizophrenia. So there are very minimum unknowns as we say for this indication. As we go market our big dementia market is a very big market. As we all know, there are a lot of chronic treatment being done up to treat these patients. But what we get to hear all the time is that you need an optimal treatment whenever there is a breakout of their agitation for the dementia patients when they are in the nursing home or they end up in the year. If TRN use, it could be very valuable as you heard today from our experts and particularly from doctor growth, but there is a huge need for this population. So we continue to build our plan and we'll roll it out that one as a check-in plan after schizophrenia and bipolar. And 4 period withdrawal, it's very clear this mechanism FDA like. They approved the drug last year, lucimura. And that's a very fast path for us to get to the NDA, because these trials are very short and they can be conducted and endpoints are well defined. It's called as cows. And with our IVTAC, we have seen that 100% reduction in cow's growth. So we have a good proof of concept there to move the drug in that direction. And we continue to work with Doctor. Maurizio and other experts to see what is the opportunity for us in the region. So I think initially company has chosen to focus on these 4 because we have a human proof of concept in all of them. And in addition, Alport withdrawal as well as CTLG are the other thing that in future can be explored. So we are as a company super excited that we have a product that is going into the Phase II and we will have the data coming out in few months by Q3 on this schizophrenia bifolders. So we will have more some of the caution that were asked about the profile of the drug. And it will allow us to power our Phase 3 trial effectively so that we can get to the business patient and file the NDA, the first NDA at the end of 2021. So basically, the second was a very high level summary of the plan for 501. Company as Bialystel Therapeutics, we work in immuno oncology area also and we have a product 701, which where we have 2 INDs approved already and 3rd already filed. And we are targeting neuroendocrine prostate cancer, which is a very big high end medical need. And pancreatic cancer has a preferred combination with our partners, NKTR-two fourteen as well as with Pfizer and mersdanstern, evelumab. So that trial will start. To I think. Company is very excited. And as a company who became a public company in last 12 months and where we are, we are very pleased with the direction we are heading and both programs are moving forward. In addition, Frank presented our simple phase, Narsiq Simple PD AI, AI is in our DNA. So we try to use AI at every stage in discovering of the drug in our translational work as well as in the clinical work. And you heard today that we are looking at digital markers to see how we can like expand the patient populations for educated patients. So we'll continue our quest for that utilizing the technology as much as we can in 3 states of discovery, foundation with us as we've been in fact So with that, I will stop and I want to give you an opportunity if you have any commercial questions. We do have Pascal here who just joined us as VP of Commercial and they've been conducting lot of key opinion leader interviews. And Reshad is our partner and she is also here and they will be happy to share with you some initial things in their market research they've been finding and they have getting the monster what was discussed there. But I think bottom line is we are trying to define the profile of the product. So we know what questions were asked to let you

• Slides